Abstract
BackgroundDiffuse intrinsic pontine gliomas (DIPGs) are highly aggressive, fatal, childhood tumors that arise in the brainstem. DIPGs have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease. New therapeutic targets are needed to develop novel therapy for DIPG.MethodsWe examined the expression of PLK1 mRNA in DIPG tumor samples through microarray analysis and found it to be up regulated versus normal pons. Using the DIPG tumor cells, we inhibited PLK1 using a clinically relevant specific inhibitor BI 6727 and evaluated the effects on, proliferation, apoptosis, induction of DNA damage and radio sensitization of the DIPG tumor cells.ResultsTreatment of DIPG cell lines with BI 6727, a new generation, highly selective inhibitor of PLK1, resulted in decreased cell proliferation and a marked increase in cellular apoptosis. Cell cycle analysis showed a significant arrest in G2-M phase and a substantial increase in cell death. Treatment also resulted in an increased γH2AX expression, indicating induction of DNA damage. PLK1 inhibition resulted in radiosensitization of DIPG cells.ConclusionThese findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of DIPG that warrants further investigation.
Highlights
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive, fatal, childhood tumors that arise in the brainstem
We show that polo-like kinase 1 (PLK1) is abnormally over expressed in DIPG compared to normal pons and that inhibition of PLK1 significantly impaired DIPG cell growth and induced DNA damage in vitro
In order to assess the significance these kinases play in the context of DIPG, we analyzed eight patient samples to determine the relative expression of a panel of mitotic checkpoint kinases versus normal brain controls
Summary
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive, fatal, childhood tumors that arise in the brainstem. Radiation therapy remains the only standard of care for this devastating disease. Diffuse intrinsic pontine glioma (DIPG) is a childhood brain tumor that is largely fatal with median survival time of just 9–12 months and accounts for the majority of pediatric brain tumor mortality [1, 2]. These tumors are highly infiltrative within the ventral pons that render them inoperable. Radiation therapy remains the standard of care [2]. A shortage of primary tissue available for research
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